Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
19503597
TITLE
Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations.
ABSTRACT
Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2x10(-201)), ABCG2 (p = 3.1x10(-26)), SLC17A1 (p = 3.0x10(-14)), SLC22A11 (p = 6.7x10(-14)), SLC22A12 (p = 2.0x10(-9)), SLC16A9 (p = 1.1x10(-8)), GCKR (p = 1.4x10(-9)), LRRC16A (p = 8.5x10(-9)), and near PDZK1 (p = 2.7x10(-9)). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0x10(-26)) and propionyl-L-carnitine (p = 5.0x10(-8)) concentrations, which in turn were associated with serum UA levels (p = 1.4x10(-57) and p = 8.1x10(-54), respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels.
DATE PUBLISHED
2009 Jun
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2009/03/05
accepted 2009/05/04
epublish 2009/06/05
entrez 2009/06/09 09:00
pubmed 2009/06/09 09:00
medline 2009/07/25 09:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Kolz M Kolz Melanie M Institute of Epidemiology, Helmholtz Zentrum München, National Research Center for Environment and Health, Neuherberg, Germany.
Johnson T Johnson Toby T
Sanna S Sanna Serena S
Teumer A Teumer Alexander A
Vitart V Vitart Veronique V
Perola M Perola Markus M
Mangino M Mangino Massimo M
Albrecht E Albrecht Eva E
Wallace C Wallace Chris C
Farrall M Farrall Martin M
Johansson A Johansson Asa A
Nyholt DR Nyholt Dale R DR
Aulchenko Y Aulchenko Yurii Y
Beckmann JS Beckmann Jacques S JS
Bergmann S Bergmann Sven S
Bochud M Bochud Murielle M
Brown M Brown Morris M
Campbell H Campbell Harry H
EUROSPAN Consortium
Connell J Connell John J
Dominiczak A Dominiczak Anna A
Homuth G Homuth Georg G
Lamina C Lamina Claudia C
McCarthy MI McCarthy Mark I MI
ENGAGE Consortium
Meitinger T Meitinger Thomas T
Mooser V Mooser Vincent V
Munroe P Munroe Patricia P
Nauck M Nauck Matthias M
Peden J Peden John J
Prokisch H Prokisch Holger H
Salo P Salo Perttu P
Salomaa V Salomaa Veikko V
Samani NJ Samani Nilesh J NJ
Schlessinger D Schlessinger David D
Uda M Uda Manuela M
Völker U Völker Uwe U
Waeber G Waeber Gérard G
Waterworth D Waterworth Dawn D
Wang-Sattler R Wang-Sattler Rui R
Wright AF Wright Alan F AF
Adamski J Adamski Jerzy J
Whitfield JB Whitfield John B JB
Gyllensten U Gyllensten Ulf U
Wilson JF Wilson James F JF
Rudan I Rudan Igor I
Pramstaller P Pramstaller Peter P
Watkins H Watkins Hugh H
PROCARDIS Consortium
Doering A Doering Angela A
Wichmann HE Wichmann H-Erich HE
KORA Study
Spector TD Spector Tim D TD
Peltonen L Peltonen Leena L
Völzke H Völzke Henry H
Nagaraja R Nagaraja Ramaiah R
Vollenweider P Vollenweider Peter P
Caulfield M Caulfield Mark M
WTCCC
Illig T Illig Thomas T
Gieger C Gieger Christian C
INVESTIGATORS
JOURNAL
VOLUME: 5
ISSUE: 6
TITLE: PLoS genetics
ISOABBREVIATION: PLoS Genet.
YEAR: 2009
MONTH: Jun
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1553-7404
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: PLoS Genet
COUNTRY: United States
ISSNLINKING: 1553-7390
NLMUNIQUEID: 101239074
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
076113/B/04/Z Wellcome Trust United Kingdom
AA007535 NIAAA NIH HHS United States
CZB/4/710 Chief Scientist Office United Kingdom
FS/05/061/19501 British Heart Foundation United Kingdom
G0400874 Medical Research Council United Kingdom
G9521010 Medical Research Council United Kingdom
G9521010D Medical Research Council United Kingdom
MC_U127561128 Medical Research Council United Kingdom
N01-AG-1-2109 NIA NIH HHS United States
PG02/128 British Heart Foundation United Kingdom
Arthritis Research UK United Kingdom
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Female
Genetic Variation
Genome-Wide Association Study
Gout etiology
Humans etiology
Male etiology
Uric Acid blood
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
268B43MJ25 Uric Acid
OTHER ID's
OTHERID SOURCE
PMC2683940 NLM